Oxidative Stress And Alcohol Metabolism Flashcards
What organ is responsible for 90% of alcohol?
Where does the rest of the alcohol go?
The liver
The rest is excreted passively in urine and on the breath
The first step in alcohol metabolism converts alcohol to what?
What enzyme is necessary to complete this step?
Alcohol—>Acetaldehyde
Alcohol dehydrogenase
The second step in alcohol metabolism converts acetaldehyde into what?
Acetaldehyde—>Acetate
Aldehyde dehydrogenase
What toxic metabolite is responsible for the “hangover” feeling ?
Acetaldehyde
Aldehyde dehydrogenase has a very ________ affinity for acetaldehyde. Why is this is of benefit?
High affinity
It keeps toxic acetaldehyde at very low levels as to not cause damage
In what situations might acetaldehyde accumulate in the liver? What can this lead to?
Prolonged, excessive alcohol consumption
Fatty Liver
Apart from the accumulation of acetaldehyde, what else can contribute to pathological changes in the liver?
Excess NADH
Increased availability of acetyl-coA
What drug can be used to treat those with a dependency to alcohol by causing “hangover” effects in those that continue to drink whilst taking it?
Disulfiram
What are ROS and RNS?
Free radicals which are atoms or molecules with one or more UNPAIRED electrons capable of independent existence
What is the problem with ROS and RNS being around the body? How to they cause damage?
They are highly reactive and generate more radials, with the potential to cause damage
Damage: Nucleic acids, proteins and lipids
How do free radials damage nucleic acids, proteins and lipids?
Nucleic acids: Cause strand break mutations in sugar cause mismatch mutation in base
Proteins: Disulphide bond formation and degradation
Lipids: Disrupt membrane integrity
What are some endogenous and exogenous sources of free radials?
Endogenous: -Electron transport chain -Nitric oxide synthases (NOS) -NADPH oxidases- (Resp. burst) Exogenous: -Radiation -Pollutants -Drugs -Toxins
Name the three most relevant free radials that might cause damage in the body
Which is the most damaging?
Superoxide O2-‘
Hydroxyl radical OH’ - MOST DAMAGING
Nitric oxide NO’ (also needed for signalling)
Hydrogen peroxide H2O2 (not a free radial but reacts to form them)
What cellular defences help to protect against free radicals?
Superoxide dismutase (SOD) / Catalase
Glutathione
Free radical scavengers - vitamin E and C
How does superoxide dismutase and catalase neutralise superoxide?
Superoxide dismutase creates H2O2 and O2 from superoxide
Catalase converts the H2O2 into H20 and O2
How does glutathione (GSH) protect against ROS?
What does this reaction require?
Donates an electron to ROS and forms a disulphide bond with another glutathione (GSH)
Requires selenium
How do vitamins E and C protect against free radicals?
They donate a H+ atom and an electron to free radicals
What is galactosaemia?
A deficiency in any of the 3 enzymes required for metabolism of galactose
How are individuals with galactosaemia susceptible to damage from free radicals?
Increased activity of aldose reductase consumes excess NADPH which compromises ROS defences and allows free radials to cause damage
What is the importance of of G6PDH deficiency in its contribution to damage by free radials?
G6PDH is a rate limiting enzyme for the pentose phosphate pathway, deficiency means there is less protection against oxidative stress causes lipid perioxidation, haemolysis and protein changes
What is the name given to the precipitation of haemoglobin as a result of G6PDH deficiency?
Heinz bodies
What is the mechanism by which paracetamol elicits its toxic effects?
Produces NAPQI which is a toxic metabolite that damages hepatocytes
Liver uses up the glutathione in an attempt to help the damage which leads to depletion
What is the antidote for paracetamol overdose?
How does this drug try to reverse the toxic effect of paracetamol?
Acetylcysteine
Replenishes the glutathione which binds to and inactivates the toxic metabolite
